DA strain of Theiler's murine encephalomyelitis virus (TMEV) causes TMEV-induced demyelinating disease (TMEV-IDD), which serves as an experimental model of multiple sclerosis (MS): both diseases have similar immune-mediated demyelinating pathology. In contrast, GDVII strain of TMEV causes a fatal encephalomyelitis without demyelination or virus persistence. Both DA L and GDVII L protein block IFN-? transcription, however, they do so at different sites in the IRF-3 pathway. DA L, and therefore DA virus infection, blocks the activation of IRF-3, while GDVII L, and therefore GDVII virus infection (as well as infection by a mutant virus called DALGDVII, in which DA L is replaced by GDVII L), activates IRF-3, but blocks the binding of IRF-3 to the IFN-? promoter. Of note, activated IRF-3: is critical for IL-27 synthesis, which inhibits Th17 cells; decreases IL-17 secretion by CD4+ memory cells; is important in the differentiation of IL-10- secreting Tr1 cells, a regulatory T cell that can resolve inflammation and restore tolerance; negatively regulates granulocyte-macrophage-colony stimulating factor (GM-CSF) expression in T cells, which is important in mediating experimental allergic encephalomyelitis (EAE). Activated IRF-3 also interferes with production of IL- 12p40, a subunit of IL-12 and IL-23, preventing polarization of nave T cells into proinflammatory Th1 cells (induced by IL-12) and Th17 cells (induced by IL-23). In the present proposal, we hypothesize that the activation or the failure of activation of IRF-3 (and the balance of IL-27/Th17) is important in the demyelination induced by TMEV, and in (partly) determining the two TMEV subgroup disease phenotypes. Antagonism of the IFN-? response because of a failure to activate IRF-3 may occur following infections with varied pathogens, and this may be the reason that the initiation of MS and/or an MS attack (or of another autoimmune disease) occurs after infection with these pathogens. A better understanding of these activities of the innate immune system in TMEV-IDD may clarify its pathogenesis and open up new therapeutic directions in MS.